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OBJECTIVES
After studying this chapter, you should be able to:
Describe the processes by which fatty acids are transported in the blood, activated and transported into the matrix of the mitochondria for breakdown to obtain energy.
Outline the β-oxidation pathway by which fatty acids are metabolized to acetyl-CoA and explain how this leads to the production of large quantities of ATP.
Identify the three compounds termed “ketone bodies” and describe the reactions by which they are formed in liver mitochondria.
Recognize that ketone bodies are important fuels for extrahepatic tissues and indicate the conditions in which their synthesis and use are favored.
Indicate the three stages in the metabolism of fatty acids where ketogenesis is regulated.
Indicate that overproduction of ketone bodies leads to ketosis and, if prolonged, ketoacidosis, and identify pathologic conditions when this occurs.
Give examples of diseases associated with impaired fatty acid oxidation.
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BIOMEDICAL IMPORTANCE
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Fatty acids are broken down in mitochondria by oxidation to acetyl-CoA in a process that generates large amounts of energy. When this pathway is proceeding at a high rate, three compounds, acetoacetate, D-3-hydroxybutyrate, and acetone, known collectively as the ketone bodies, are produced by the liver. Acetoacetate and D-3-hydroxybutyrate are used as fuels by extrahepatic tissues in normal metabolism, but overproduction of ketone bodies causes ketosis. Increased fatty acid oxidation and consequently ketosis is a characteristic of starvation and of diabetes mellitus. Since ketone bodies are acidic, when they are produced in excess over long periods, as in diabetes, they cause ketoacidosis, which is ultimately fatal. Because gluconeogenesis is dependent on fatty acid oxidation, any impairment in fatty acid oxidation leads to hypoglycemia. This occurs in various states of carnitine deficiency or deficiency of essential enzymes in fatty acid oxidation, for example, carnitine palmitoyltransferase, or inhibition of fatty acid oxidation by poisons, for example, hypoglycin.
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OXIDATION OF FATTY ACIDS OCCURS IN MITOCHONDRIA
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Although acetyl-CoA is both an end point of fatty acid catabolism and the starting substrate for fatty acid synthesis, breakdown is not simply the reverse of the biosynthetic pathway, but an entirely separate process taking place in a different compartment of the cell. The separation of fatty acid oxidation in mitochondria from biosynthesis in the cytosol allows each process to be individually controlled and integrated with tissue requirements. Each step in fatty acid oxidation involves acyl-CoA derivatives, is catalyzed by separate enzymes, utilizes NAD+ and FAD as coenzymes, and generates ATP. It is an aerobic process, requiring the presence of oxygen.
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Fatty Acids Are Transported in the Blood as Free Fatty Acids
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Free fatty acids (FFAs)—also called unesterified (UFA) or nonesterified (NEFA) fatty acids (see Chapter 21)—are fatty acids that are in the unesterified state. In plasma, longer-chain FFA are combined with albumin, and in ...